JP5764281B2 - Blood fluidity improver - Google Patents

Description

  The present invention relates to a composition for improving blood fluidity (blood rheology). The present invention relates to a technical field such as a blood disease preventive agent and a thrombosis preventive agent by increasing blood fluidity.

1. Blood fluidity and measurement method The ease of blood flow in a blood vessel is naturally influenced by the contraction of the blood vessel, but is greatly influenced by the characteristics of the blood itself as a fluid. Blood can be divided into blood cell components such as red blood cells, white blood cells, and platelets, and plasma components containing various proteins, lipids, minerals, and the like. Blood fluidity, in other words, blood viscosity, is thought to be particularly affected by red blood cell volume and deformability (the ability to flexibly deform and pass through narrow spaces), plasma fibrinogen, white blood cells, and platelets. . Currently, a device for measuring the fluidity of collected blood (MC-FAN: Micro Channel array Flow Analyzer) has been developed, which can measure the fluidity of blood (Non-Patent Documents 1 to 3). .

2. Blood fluidity improving agent that affects blood fluidity Research and development have been conducted on compounds and / or compositions that affect blood fluidity. For example, it has been reported that when a fruit acid supplement is ingested during a long-distance running, an increase in blood viscosity when further running is suppressed (Non-patent Document 4).

  In addition, 10 long-distance runners were allowed to drink 20 ml of black vinegar every day for 30 days, and vascular function tests and blood collection were conducted on the day before the start of drinking and the day after the last drinking. It has been reported that (VEGF) and MCHC were significantly reduced by drinking black vinegar, and MCV was significantly increased. The enhancement of red blood cell deformability of black vinegar improves the microcirculation, and the increase of blood fluidity by black vinegar increases the blood flow to active muscles, that is, the amount of oxygen transport, and is thought to contribute to the improvement of endurance exercise capacity. (Non-Patent Document 5).

Furthermore, Patent Document 1 includes L-glutamine 8 to 27 parts by mass, L-arginine 6 to 21 parts by mass, L-leucine 8 to 25 parts by mass, L-isoleucine 6 to 20 parts by mass, and L-valine 6 to 19 parts. Contains 5 parts by mass of amino acids as essential components (L-glutamine 0.34g, L-arginine 0.34g, L-leucine 0.28g, L-isoleucine 0.18g, L-valine 0.18g, L-lysine 0.14g, L Oral amino acid composition containing 0.12 g of methionine, 0.18 g of L-threonine, 0.10 g of L-histidine, 0.10 g of L-proline, 0.01 g of L-phenylalanine and 0.03 g of L-tryptophan) It is described that the blood fluidity was improved by taking 1 bag 3 times a day after each meal (3.96g as 5 essential amino acids).
JP 2005-272410 A BRAIN Techno News, No. 86, Jul 15, 2001 Microvasc. Res. 44: 226-240, 1992 Microvasc. Res. Jan; 47 (1): 126-39, 1994 Journal of the Japan Society of Hemorheology, 2003, Vol. 6, No. 2, pp. 83-88 Journal of the Japan Society of Hemorheology, 2004, Vol. 7, No. 1, pp. 25-31

  All of the conventional technologies are related to improving blood fluidity under special conditions such as athletes running long distances, and many of them are the first to take drugs or compounds that lower blood viscosity for a long time. The effect has been confirmed.

  This invention makes it a subject to develop the blood viscosity reducing agent which has an immediate effect in normal life in healthy persons other than an athlete.

  The present inventors have found that a specific amino acid composition exhibits an effect of lowering blood viscosity immediately after oral intake by a normal healthy person, and completed the present invention.

  The invention of the present application is highly safe and commonly used for normal eating and drinking, and by using inexpensive amino acids with a specific composition, thrombosis, hypertension, etc., which are expected to increase with the aging of society in the future It has an excellent effect that it is useful for the treatment and / or prevention of diseases associated with a decrease in blood flow fluidity.

  This specification includes the contents described in the specification and / or drawings of Japanese Patent Application No. 2006-159901, which is the basis for the priority of the present application.

An outline of the experimental method and the relationship between the time of ingestion of amino acids and the time of first and second blood sampling are shown. Effect on blood flow by drinking VAAM (amino acid drink) (190g). The same No. indicates the same subject. Influence on blood flow by VAAM (amino acid drink) drinking (190g) (n = 10), average of 10 subjects. Before ingestion; 45.4 ± 4.4 (seconds), after ingestion; 41.6 ± 3.2 (seconds) (mean ± S.D.); **: p <0.01 VAAM Mix. Effects on the blood flow of each of 6 subjects by drinking (amino acid weight 3 g). VAAM Mix. Average blood flow effect (n = 6) of drinking (amino acid weight 3g). The blood flow time was 45.0 ± 1.9 (seconds) before ingestion, but was shortened to 42.8 ± 1.8 (seconds) (mean ± S.D.) After ingestion. **: p <0.01 Effects of BCAA drinking (amino acid weight 3g) on blood flow of 6 subjects. Average blood flow effect (n = 6) of BCAA drinking (amino acid weight 3g). The blood flow time was 41.1 ± 2.7 (seconds) before ingestion, but after ingestion: 39.8 ± 2.4 (seconds) (mean ± S.D.). Effects on the blood flow of each of 6 subjects by CAAM drinking (amino acid weight 3 g). Average of blood flow effect (n = 6) by CAAM drinking (amino acid weight 3g). The blood flow time hardly changed from 41.6 ± 3.0 (seconds) before ingestion to 41.4 ± 1.2 (seconds) (mean ± S.D.) After ingestion.

1. Blood fluidity or blood viscosity and disease Blood viscosity is considered a risk factor for cardiovascular disease. In the arterial system, as blood viscosity increases, blood pressure increases to maintain blood flow to the tissue. In the venous system, if the blood flow volume decreases as the blood viscosity increases, the shear rate decreases, so the blood viscosity increases and the blood flow volume further decreases. Such circulatory disturbance caused by an increase in blood viscosity is called hyperviscosity syndrome, and is said to be lying at the bottom of various diseases (Nippon Physiology Magazine, Vol. 66, pp. 234-244).

The food and drink containing the blood flow improving agent or blood viscosity reducing agent and blood fluidity improving agent or blood viscosity reducing agent of the present invention is a cardiovascular system including hypertension, thrombosis, shoulder stiffness, coldness, infarction, diseases caused by blood circulation disorder, blood disorder of peripheral or central, such as arterial sclerosis, by improving blood flow fluidity, can be prevented and / or treated.

  The blood fluidity can be measured using, for example, a liquid fluidity measurement device (MC-FAN: Micro Channel Array Flow Analyzer, MC Laboratory Inc.). This device allows the flow of cells flowing through a channel by flowing blood through a microchannel array formed by crimping a glass substrate with microscopic grooves on a silicon chip processed using semiconductor microfabrication technology. The state is directly observed and recorded with a microscope (the company's website).

2. Improvement of blood fluidity or blood viscosity As mentioned above, since blood viscosity is a risk factor for various diseases such as cardiovascular diseases, the treatment of these diseases including cardiovascular diseases that have been increasing in recent years And / or for prevention, it is useful to develop compositions that reduce blood viscosity or improve blood fluidity. Factors that increase the blood viscosity include a decrease in erythrocyte shape deformability and erythrocyte aggregation. For example, accumulation of Ca in erythrocytes and changes in the interaction between membrane proteins resulting from this are said to contribute to essential hypertension. On the other hand, as a factor that lowers blood viscosity, for example, it is said that NO-generating substances increase erythrocyte deformability (Nippon Physiology Magazine, Vol. 66, No. 9, pp. 287-297). In addition, as described above, it has been reported that the ingestion of fruit acid or black vinegar reduces the blood viscosity of athletes during sports.

3. Composition of amino acids (Hereinafter, amino acids may be indicated by a three letter code.)
The present invention includes a blood fluidity improving agent or blood viscosity reducing agent comprising an amino acid composition containing threonine, proline, glycine, valine, isoleucine, leucine, tyrosine, phenylalanine, lysine, methionine, tryptophan, histidine and arginine as an active ingredient. Includes agents.

  The present invention also includes an amino acid composition containing aspartic acid, serine, glutamic acid and alanine in addition to threonine, proline, glycine, valine, isoleucine, leucine, tyrosine, phenylalanine, lysine, methionine, tryptophan, histidine and arginine. A blood fluidity improving agent or blood viscosity reducing agent contained as an active ingredient is included.

  Specifically, the present invention improves blood fluidity containing an amino acid composition comprising threonine, proline, glycine, valine, isoleucine, leucine, tyrosine, phenylalanine, lysine, methionine, tryptophan, histidine and arginine as an active ingredient. Agents or blood viscosity reducing agents.

  Further, the present invention specifically includes an amino acid comprising threonine, proline, glycine, valine, isoleucine, leucine, tyrosine, phenylalanine, lysine, methionine, tryptophan, histidine, arginine, aspartic acid, serine, glutamic acid, and alanine. A blood fluidity improving agent or blood viscosity reducing agent containing the composition as an active ingredient is included.

  Each amino acid constituting the amino acid composition of the present invention may be a free amino acid or a pharmaceutically or food acceptable salt. For example, each amino acid may be hydrochloride, lactate, and the like.

  Examples of the amino composition of the present application include the following.

3-1. A blood fluidity improving agent or blood viscosity reducing agent comprising an amino acid composition comprising threonine, proline, glycine, valine, isoleucine, leucine, tyrosine, phenylalanine, lysine, methionine, tryptophan, histidine and arginine as an active ingredient.

  In the present invention, an amino acid composition comprising threonine, proline, glycine, valine, isoleucine, leucine, tyrosine, phenylalanine, lysine, methionine, tryptophan, histidine, and arginine as an active ingredient, and amino acid as a weight ratio, 2-15 mol, 4-30 mol proline, 7-20 mol glycine, 4-8 mol valine, 3-9 mol isoleucine, 2-12 mol leucine, 1-9 mol tyrosine, 0.5 phenylalanine A blood fluidity-improving agent or blood viscosity-decreasing agent characterized by containing -5 mol, lysine in a proportion of 5-11 mol, and containing methionine, tryptophan, histidine, arginine in a proportion of 5 mol or less. Is included.

3-2. Improved blood fluidity containing an amino acid composition consisting of threonine, proline, glycine, valine, isoleucine, leucine, tyrosine, phenylalanine, lysine, methionine, tryptophan, histidine, arginine, aspartic acid, serine, glutamic acid, and alanine as active ingredients Agent or blood viscosity reducing agent.

  In the present invention, the amino acids are in a weight ratio of 2 to 15 mol of threonion, 4 to 30 mol of proline, 7 to 20 mol of glycine, 4 to 8 mol of valine, 3 to 9 mol of isoleucine, and 2 of leucine. -12 mol, tyrosine 1-9 mol, phenylalanine 0.5-5 mol, lysine 5-11 mol in a proportion of 5 mol or less, each containing methionine, tryptophan, histidine, arginine, Blood fluidity improving agent or blood viscosity comprising as an active ingredient an amino acid composition comprising aspartic acid in a proportion of 1 mol or less, serine in a proportion of 5 mol or less, glutamic acid in a proportion of 4 mol or less, alanine in a proportion of 12 mol or less. A reducing agent is included.

  More specifically, the present invention includes 6.92% by weight of threonion, 16.79% by weight of proline, 11.60% by weight of glycine, 5.56% by weight of valine, 4.79% by weight of isoleucine, 6.53% by weight of leucine, 6.93% by weight of tyrosine. Wt%, phenylalanine 5.12 wt%, lysine 12.75 wt% as lysine hydrochloride, methionine 0.64 wt%, tryptophan 3.63 wt%, histidine 3.23 wt%, arginine 4.96 wt%, aspartic acid Na aspartate 0.22 A blood fluidity improving agent or blood viscosity reducing agent comprising an amino acid composition consisting of 2% by weight, 2.11% by weight of serine, 3.81% by weight of glutamic acid, and 4.41% by weight of alanine is included.

4). Form of use of the composition of the present invention The form of use of the amino acid composition of the present invention is not particularly limited, but can be used for medical purposes, food and drink, and nutritional supplement food and drink.

  For medical use, it can be used by general administration routes such as oral administration, rectal administration, injection, and administration by infusion. In the case of oral administration, it may be mixed with the above composition itself or a pharmaceutically acceptable carrier, excipient, diluent, etc. to form a powder, granule, tablet, capsule, troche, syrup, etc. it can. As an injection, an appropriate buffer, an isotonic agent or the like added and dissolved in sterilized distilled water may be used.

  Since the composition of the present invention is extremely safe, its dosage can be set in a very wide range, and further varies depending on the administration method and purpose of use, but usually 0.5 to 5 g at a time, 1 to 20 g as a daily dosage. , Preferably 5 to 10 g. In the case of these solutions, a single dose may be 10 to 1000 ml as a 0.5 to 10 wt% solution, preferably 100 to 400 ml as a 1 to 4 wt% solution.

  In the case of edible use, the present amino acid composition can be edible as it is, but can also be used as an additive to various foods. In addition, the composition of the present invention can be dissolved in water to make a beverage. In this case, other nutritional components such as aqueous vitamins and taurine can be further added. Moreover, in order to improve palatability, it can also be set as a drink by adding salts, such as sodium chloride, acids, such as a citric acid, and / or other suitable flavors. A pH adjusting agent and a chelating agent can be further added for stability.

[Example 1] Confirmation of blood flow improvement effect when an amino acid beverage (VAAM) was consumed An amino acid beverage (VAAM, 190 g, Meiji Dairies) was used as a sample, and water (190 g) was used as a placebo. In amino acid beverage 1, as amino acids, AspNa · H ₂ O 7 mg, Thr 207 mg, Ser 63 mg, Glu 114 mg, Gly 347 mg, Ala 132 mg, Val 166 mg, Met 19 mg, Ile 143 mg, Leu 196 mg, Tyr 208 mg, Phe 153 mg, Trp 109 mg, LysHCl 382 mg, His 97 mg, Arg 149 mg, and Pro 503 mg.

  Blood was collected from 10 subjects once before ingesting the sample. The sample was drunk immediately after blood collection, and blood was collected again after 1 hour. During this one hour, the subject was at rest. The time table of the experiment is shown in FIG. The blood passage time before and after drinking the sample was measured and compared to confirm the blood flow improvement effect. A placebo test (drinking water) was further conducted in 4 of 10 subjects.

  Blood was collected by adding 0.25 ml of heparin (5% of the whole blood) in advance to a vacuum blood collection tube, and collecting 5 ml from the subject. The obtained fresh blood was immediately used as a measurement sample. MC-FAN (Micro Channel Array Flow Analyzer) was used for the measurement. In MC-FAN, the pressure of 20 cm water column was applied to the channel system, and the flow rate of 100 μl of whole blood was measured under this constant pressure. Variation at each measurement was corrected by measuring the flow rate of 100 μl of physiological saline at each measurement. Bloody 6-7 (chip size: 15 mm x 15 mm, thickness: 500 μm, flow path: width x length x depth = 7 μm x 30 μm x 4.5 μm) was used as the microchip to be mounted on the MC-FAN. .

(result)
Ten subjects were evaluated for blood flow improvement effect of amino acid beverage (VAAM). As a result, blood flow time was shortened in 8 people, and no change was seen in the remaining 2 people (FIG. 2). There was no change in blood flow time in the 3 patients in the placebo group, but there was a significant increase in 1 patient. It is reasonable to think that this one is clearly irregular measurement. The blood flow time of 100 μl before drinking was 45.4 ± 4.4 seconds (mean ± SD), but 41.6 ± 3.2 seconds after drinking 1 hour, which was significantly shortened (student's t-test) (Figure 3). On the other hand, drinking water did not affect blood fluidity. That is, it can be inferred that the blood flow improvement effect observed by a single intake of an amino acid beverage (VAAM) is due to an amino acid mixture as an active ingredient of VAAM.

[Example 2] Confirmation of blood fluidity improvement effect when ingesting amino acid mixture (VAAM Mix.) An amino acid mixture (VAAM Mix.) (3.0 g, Meiji Dairies) was used as a sample. In VAAM Mix., Asp 7mg, Thr 207mg, Ser 63mg, Glu 114mg, Gly 347mg, Ala 132mg, Val 166mg, Met 19mg, Ile 143mg, Leu 196mg, Tyr as amino acids Contains 208 mg, Phe 153 mg, Trp 109 mg, LysHCl 382 mg, His 97 mg, Arg 149 mg, and Pro 503 mg. This was wrapped in oblate (manufactured by Pip Tokyo Co., Ltd.) and allowed to be drunk by 6 subjects with 50 g of soft water. The composition (% by weight) of VAAM Mix. Is as shown in Table 1.

  Blood was collected from 6 subjects once before taking the sample. The sample was drunk immediately after blood collection, and blood was collected again after 1 hour. During this one hour, the subject was at rest. The blood passage time before and after drinking the sample was measured and compared to confirm the blood flow improvement effect. Each blood sample was measured twice.

  Blood was collected by adding 0.25 ml of heparin (5% of the whole blood) to the vacuum blood collection tube in advance and collecting 5 ml from the subject. The obtained fresh blood was immediately used as a measurement sample. MC-FAN (Micro Channel Array Flow Analyzer) was used for the measurement. In MC-FAN, the pressure of 20 cm water column was applied to the channel system, and the flow rate of 100 μl of whole blood was measured under this constant pressure. Variation at each measurement was corrected by measuring the flow rate of 100 μl of physiological saline at each measurement. Bloody 6-7 (chip size: 15 mm x 15 mm, thickness: 500 μm, flow path: width x length x depth = 7 μm x 30 μm x 4.5 μm) was used as the microchip to be mounted on the MC-FAN. .

(result)
When VAAM Mix. Was taken, blood flow time was shortened in all six subjects (FIG. 4). The blood flow time of 100 μl before sample intake was 45.0 ± 1.9 seconds (mean ± SD), but 42.8 ± 1.8 seconds after intake 1 hour, which was significantly shortened (student's t-test) (FIG. 5). In the examination so far, the blood flow improvement effect of the amino acid drink (VAAM, Meiji Dairies) has been confirmed. In this study, it was considered that amino acids contributed to the blood flow improvement effect of VAAM because the blood flow improvement effect was observed by drinking the amino acid mixture (Mix.).

Comparative example

  As a sample, an amino acid mixture (BCAA and CAAM) (3.0 g, supplied by Meiji Dairies Co., Ltd.) was used. The sample was wrapped in an oblate (manufactured by Pip Tokyo Co., Ltd.) and drunk by 6 subjects with 50 g of soft water. In BCAA, valine was 750 mg, leucine was 1500 mg, and isoleucine was 750 mg. The composition (% by weight) of CAAM is as shown in Table 2.

  Blood was collected once before drinking the sample. The sample was drunk immediately after blood collection, and blood was collected again after 1 hour. During this one hour, the subject was at rest. The blood passage time before and after drinking the sample was measured and compared to confirm the blood flow improvement effect. Blood was collected by adding 0.25 ml of heparin (5% of the whole blood) in advance to a vacuum blood collection tube, and collecting 5 ml from the subject. The obtained fresh blood was immediately used as a measurement sample.

(result)
When BCAA was taken, blood flow time was shortened in 4 subjects and prolonged in 2 subjects (FIG. 6). The blood flow time of 100 μl before sample ingestion was 41.1 ± 2.7 seconds, whereas it was 39.8 ± 2.4 seconds 1 hour after ingestion, and there was no significant difference in blood flow time (FIG. 7).

When CAAM was consumed, blood flow time was shortened in 3 subjects and increased in 3 subjects (FIG. 8). The blood flow time of 100 μl before sample ingestion was 41.6 ± 3.0 seconds, but 41.4 ± 1.2 seconds 1 hour after ingestion, and no significant difference was observed in blood flow time (FIG. 9).

  The present invention can be used in the fields of food, beverages, dietary supplements and medicine.

  All publications, patents and patent applications cited herein are incorporated herein by reference in their entirety.

Claims (2)

Amino acid composition , 2-15 mol of threonion, 4-30 mol of proline, 7-20 mol of glycine, 4-8 mol of valine, 3-9 mol of isoleucine, 2-12 mol of leucine, tyrosine 1 to 9 mol, phenylalanine 0.5 to 5 mol, lysine 5 to 11 mol, and 5 mol or less, each containing methionine, tryptophan, histidine, arginine, and 1 mol or less A blood fluidity improving agent or a blood viscosity reducing agent comprising: aspartic acid in a proportion, serine in a proportion of 5 mol or less, glutamic acid in a proportion of 4 mol or less, alanine in a proportion of 12 mol or less . A blood fluidity improving agent or blood viscosity reducing agent, wherein 0.5 to 5 g of the amino acid composition according to claim 1 is administered at a time.

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